1. Field of the Invention
This invention relates broadly to articles of manufacture for administration of pharmacologically active substances, transdermally and by means of implant (e.g., subdermal implant). More specifically, this invention relates to articles for the controlled release and delivery to animal tissue (including but not limited to epidermal tissue) of a composition of matter comprising at least one pharmacologically active agent with or without one or more excipients therefor and/or one or more enhancers therefor at least one of said pharmacologically active agents, excipients therefor and enhancers therefor being a causative factor in the occurrence of non-allergic or allergic contact dermatitis comprising an anti-dermatitic substance having a chemical constituency different from that of the chemical constituency of any of said pharmacologically active agents, any of said excipients therefor, or any of said enhancers therefor.
The articles of our invention may be in the form of transdermal controlled release systems wherein the reservoir for the pharmacologically active agent is a solid polymer, or a transdermal delivery device wherein the pharmacologically agent is delivered from for example, a gel through a microporous membrane to the tissue to be treated, or the control release article may be a dispenser for delivering a pharmacologically active agent contained in a heat-responsive composition using an osmotically effective solute, through a passageway from the dispenser. The anti-dermatitic substance may be, for example:
(a) corticosteroids; PA1 (b) chemicals that compete with the arachidonic acid biotransformation; PA1 (c) inhibitor substances for the arachidonic acid cascade; PA1 (d) free radical scavenger substances; PA1 (e) Vitamin E; PA1 (f) nordihydroguaiaretic acid; PA1 (g) Vitamin D; or PA1 (h) leukotriene receptor antagonists PA1 (a) guanfacine; PA1 (b) (5Z, 13E, 15R, 16R)-16-fluoro-15-hydroxy-9-oxoprosta-5-dienoic acid; PA1 (c) fluphenazine; and PA1 (d) clonidine. PA1 "An anti-inflammatory and analgesic transdermal tape contains diclofenac sodium and an organic acid such as citric acid. Diclofenac sodium is readily absorbed by the skin from this tape in the presence of the acid. Thus, 2-ethylhexyl acrylate 55, methoxyethyl acrylate 30, vinyl acetate 15, and azobisisobutyronitrile 0.3 parts by weight were mixed and heated at 60.degree.-63.degree. in 125 parts of ethyl acetate for ten hours and the polymer was cured for two hours at 80.degree. C. Diclofenac sodium and citric acid were added in such a way that the concentrations in the formulation after drying were 20 and 4% by weight respectively. The mixture was applied to a removable liner to give a tape containing 400 micrograms diclofenac sodium per square centimeter." PA1 "A penetration-enhancing pharmaceutical composition for topical application comprising: PA1 wherein component (d)(i) and (d)(ii) are present in a ratio of (d)(i):(d)(ii) of about 5:1 to about 100:1 by weight." PA1 "A penetration-enhancing pharmaceutical composition for topical application comprising: PA1 "Esters of methyl salicylate with certain non-steroidal anti-inflammatory drugs (NSAID's) can be used for topical administration to mammals, to elicit a response which combines the anti-inflammatory and analgesic effects of the NSAID and the counter-irritant effect of the methyl salicylate. Typical NSAID's which can be used in this way are aspirin (acetylsalicic acid), ibuprofen and indomethacin. Advantageously, the NSAID-methyl salicylate ester is administered in the form of a pharmaceutical composition, such as an ointment, gel, lotion, cream or the like." PA1 (a) corticosteroids; PA1 (b) chemicals that compete with the arachiodonic acid biotransformation; PA1 (c) inhibitor substances of the arachiodonic acid cascade; PA1 (d) free radical scavenger substances; PA1 (e) Vitamin E; PA1 (f) nordihydroguaiaretic acid; PA1 (g) Vitamin D; and PA1 (h) leukotriene receptor antagonists. PA1 (a) a polymer layer (for example, a polyvinyl chloride-polyvinyl acetate layer); PA1 (b) one or more pharmacologically active agents with or without one or more excipients therefor or one or more enhancers therefor, at least one of which is a causative factor in the occurrence of non-allergic or allergic contact dermatitis and each of which is chemically compatible with said polymer, in intimate admixture with said polymer; and PA1 (c) at least one anti-dermatitic substance chemically compatible with (i) one or more of said pharmacologically active agents, one or more excipients therefor and one or more enhancers therefor; and (ii) said polymer and said anti-dermatitic substance being in intimate admixture with said polymer and/or one or more of said pharmacologically active agents, one or more excipients therefor and/or one or more enhancers therefor.
or combinations thereof. Pharmacologically active substances which are known to cause contact dermatitis are, for example,
2. The prior Art
Relatively intensive efforts are currently being expended in the pharmaceutical industry to provide for the delivery, in a controlled release manner, of pharmacologically active agents to the skin, and to mucous membranes of animals without the causation of allergic or non-allergic contact dermatitis and without the causation of subdermal inflammation of the tissues being treated by the pharmacologically active agent.
Thus, for example, U.S. Pat. No. 4,668,510 issued on May 26, 1987 and U.S. Pat. No. 4,576,818 provide iodophors which exhibit effective degerming of skin, and mucous membranes of animals and which provide broad spectrum microbiocidal action without toxicity or irritation. The prior art includes evidence of a great effort to provide controlled release formulations which provide anti-inflammatory and analgesic products to the skin.
Thus, Japan Kokai 85/122,291 published on Dec. 11, 1986 and abstracted at Chemical Abstracts, Vol. 106, No. 125909s discloses a transdermal tape containing diclofenac sodium as the active ingredient in an anti-inflammatory and analgesic transdermal tape having a soft pressure sensitive adhesive layer. The abstract state:
South African Patent 8410-058 and German Offenlegungsschrift 33 47 278A published on June 24, 1985 disclose prolonged percutaneous release compositions containing an active substance, preferably by anti-inflammatory agent in an elastomer mixture consisting of diene rubbers. By the same token, South African Patent 8410-059 and German Offenlegungsschrift 33 47 277 published on Dec. 27, 1984 disclose prolonged percutaneous release compositions containing an active substance, preferably an anti-inflammatory agent in an elastomer mixture consisting of amorphous olefinic copolymers.
Canadian Letters Patent 1,223,818 issued on July 7, 1987 and 1,223,819 issued on July 7, 1987 disclose penetrating topical pharmaceutical compositions containing N-(2-hydroxyethyl)-pyrrolidone and 1-dodecyl-azacycloheptan-2-one. More specifically, Canadian Letters Patent 1,223,818 discloses and claims:
(a) about 0.01% to about 10%, by weight, of a non-steroidal anti-inflammatory agent selected from the group consisting of salicylic acid, acetyl salicylic acid, methyl salicylate, glycol salicylate, salicylmides, benzyl-2,5-diacetoxybenzoic acid, ibuproten, fulindac, naproxen, keto-profen, etofenamate, phenylbutazone, indomethacin, piroxican, and mixtures thereof; PA2 (b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol; PA2 (c) 0% to about 80% by weight water; PA2 (d) about 10% to about 99.9% by weight of a penetration-enhancing vehicle consisting essentially of: PA2 (a) about 0.01% to about 10%, by weight, of a non-steroidal anti-inflammatory agent selected from the group consisting of salicylic acid, acetyl salicylic acid, methyl salicylate, glycol salicylate, salicylmides, benzyl-2,5-diacetoxybenzoic acid, ibuprofen, fulindac, naproxen, keto-profen, etofenamate, phenylbutazone, indomethacin, piroxicam, and mixtures thereof; PA2 (b) 0% to about 80% by weight of a solvent selected from ethanol and 2-propanol; PA2 (c) 0% to about 80% by weight water; PA2 (d) about 25% to about 96% by weight of a penetration-enhancing diol or cycloketo compound selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, pyrrolidone, 1-(2-hydroxyethyl)azacyclopentan-2-one, and mixtures thereof; and PA2 (e) about 1.0% to about 35% by weight of 1-dodecylazacycloheptan-2-one."
(i) N-(2-hydroxyethyl)pyrrolidone, and PA3 (ii) a cell-envelope disordering compound selected from the group consisting of methyl laurate, oleic acid, oleyl alcohol, monoolein, myristyl alcohol, and mixtures thereof;
More specifically, Canadian Letters Patent 1,223,819 discloses and claims:
Bonney, et al, Arzneim.-Forsch, 35(4), pages 715-720 (abstracted at Chemical Abstracts, Vol. 103, No. 81418h) discloses the use of 2-(3-(1,1-dimethylethyl)-5-methoxy phenyloxazolo (4,5-b)pyridine as a topical anti-inflammatory and analgesic compound lacking systemic activity and gastric side effects. It is indicated that this compound is as potent as indomethacin in inhibiting ultra-violet light-induced erythema in guinea pig skin and it is further indicated that this compound is an effective analgesic when applied topically to the rat footpad. It is further indicated that the compound is a cyclooxygenase inhibitor and an inhibitor of prostaglandin E2 but not leukotriene C4 synthesis.
Tsukada, et al, Arzneim.-Forsch, 28(3), pages 428.gtoreq.438 discloses the anti-inflammatory, analgesic, anti-pyretic and other pharmacological effects of osepinao-(6,11-dihydro-11-oxodibenz(b,e)oxepin-3-acetic acid and compared the effects with know non-steroidal anti-inflammatory drugs such as indomethacin.